The selective BTK inhibitor zanubrutinib (Brukinsa) has been approved by the TGA for the treatment of adult patients with Waldenström’s macroglobulinemia (WM) and mantle cell lymphoma (MCL).

Both groups of patients will have immediate access to the drug through a BeiGene sponsored post-approval, pre-reimbursement access program.

Zanubrutinib has been approved for WM patients who have received at least one prior therapy, or as a first-line treatment for patients unsuitable for chemoimmunotherapy.

The TGA approval was supported by clinical trial evidence including the head-to-head ASPEN study comparing zanubrutinib to ibrutinib in WM, as previously published in Blood and reported in the limbic.

The study found a modest but not significant improvement in the rate of very good partial response (VGPR) in patients treated with zanubrutinib compared to ibrutinib (28% v 19%; p=0.09).

Professor Con Tam, Program Lead for CLL and Low-Grade Lymphoma at the Peter MacCallum Cancer Centre, told the limbic ASPEN was technically a negative study but the investigators were confident it would become a positive study with further follow-up.

“Although the primary endpoint was negative at this stage, there were multiple indicators that zanubrutinib may be more effective and with further follow up would see differences in PFS.”

Professor Tam said zanubrutiniib was unquestionably safer than the first generation drugs.

“In a direct head-to-head comparison, all the adverse events were reduced including AEs leading to death, AEs leading to treatment discontinuation or AEs leading to dose reduction,” he said.

“Essentially the individual AEs were all much reduced in zanubrutinib. In particular the rate of AF was 7-fold lower with zanubrutinib compared to ibrutinib.”

“There is no doubt that zanubrutinib is a safer drug in terms of AF, hypertension and probably in terms of bleeding as well compared to ibrutinib.”

He said together with subsequent studies – the ALPINE study of zanubrutinib in CLL and the ELEVATE study of acalabrutinib – all three head to head comparisons between a second and first generation drug showed a reduction in AF and hypertension.

“In aggregate, second generation drugs are undoubtedly safer than the first generation drugs in terms of AF and hypertension, and may be more effective or at least as effective … but we need further follow-up.”

He said the only disadvantage of second generation drugs was the requirement for twice daily dosing compared to once daily dosing.

Mantle cell lymphoma

Professor Tam said the approval for zanubrutinib in MCL followed FDA approval based on two single arm studies.

“The phase 1/2 study in multiple diseases in Australia in both front line and relapse settings showed a high response rate and PFS of approximately 18 months.”

“A second Chinese study also had a very high response rate and CR rate of 60-70%.”

Professor Tam said more evidence in MCL was coming in the phase 3 zanubrutinib plus rituximab versus bendamustine plus rituximab trial which was currently recruiting.

He said ibrutinib was still the standard of care given it had the longest followup.

“And certainly if my patients are doing well on ibrutinib, I wouldn’t switch them over. For most new patients there is no reason not to use the second generation drugs…especially if AF is a risk or in patients with poor tolerance because they have high blood pressure or preexisting heart disease,” he said.

Professor Tam said most haematologists were aware of zanubrutiniib especially as the first 25 patients in the world were treated entirely in Melbourne.

Disclosure: Professor Tam receives research funding and honoraria from pharmaceutical companies including BeiGene.